Major psychiatric illnesses such as schizophrenia, bipolar disorder and depression are complex diseases caused by the interaction of genetic and environmental factors. These influences intersect at the level of gene expression and create complex phenotypes that are the result of collective influences by groups of genes acting in concert across different brain regions. This study will investigate the dentate gyrus (DG) of the hippocampus and use large-scale gene expression profiling to model the regulatory relationships between genes in nearly homogeneous populations of DG granule cells. We hypothesize that disruption in the serotonin system by genetic polymorphisms of the serotonin transporter (SERT) gene results in alterations in gene expression in the dentate gyrus (DG) of the hippocampus which contribute to psychiatric disorders. We will compare gene regulatory networks in the DG in postmortem brain tissue from healthy and mentally ill subjects, and in mentally healthy carriers of different SERT haplotypes. This will allow us to test the hypothesis that certain SERT polymorphisms can raise the risk for mental illness by interfering with local patterns of gene expression. Homogeneous cell populations of dentate gyrus granule cells from mid-hippocampus will be harvested using laser capture microdissection, aRNA amplification, and hybridization to Affymetrix oligonucleotide microarrays. Gene expression profiles will be used to create models of gene regulatory networks in the DG. These models will allow us to make predictions about key regulatory elements in the DG gene network, and these predictions will be tested by quantitative RT-PCR. Relevance of this research to public health: Major psychiatric illnesses are chronic diseases that carry a very heavy disease burden both in terms of human suffering and as financial losses due to treatment costs and lost productivity. Previous genetic association studies have shown that allelic variants of SERT can influence disease risk in combination with environmental factors. In this study we will compare gene expression between groups of subjects with major psychiatric illnesses and normal controls, model the interaction of genes in a gene regulatory network, and identify key regulatory elements where genetic and environmental influences can intersect. This will increase our understanding of genetic risk factors for mental illness, gene-environment interactions, and highlight possible new treatment strategies.